Lentiviruses such as human immunodeficiency virus are able to infect terminally differentiated/non-dividing cells, e.g., macrophages, as well as dividing activated CD4+ T cells. Upon infection, viral genomic RNA is replicated into double stranded proviral DNA by a virally encoded DNA polymerase, reverse transcriptase (RT). Non-dividing cells harbor strikingly low cellular dNTP concentrations (20-40 nM) as compared to activated CD4+ T cells (1-4 μM). Such limited cellular dNTP levels impose a kinetic stress on retroviral DNA synthesis catalyzed by viral RT in non-dividing cells.
Despite the replication barriers present in non-dividing cells, infection of non-dividing cells are a critical feature of retrovirus pathogenesis. For example, despite the strides that have been made in treating retrovirus infections, non-dividing cells remain a source of long-lived productive reservoirs of retrovirus infection in vivo. Accordingly, in order to improve current methods for preventing and treating retrovirus infection in non-dividing cells, there is a need to better understand how retroviruses are able to replicate in such a cellular environment. In particular, it is desirable to fully characterize the effects of the limited cellular dNTP levels in non-dividing cells on viral RT.